Porphyrenediynes: synthesis and cyclization of meso-enediynylporphyrins

Article abstract of DOI:10.1016/j.tetlet.2006.10.164

Synthetic methodology to prepare porphyrinylethynyl enediynes has been developed. Compared to phenylethynyl derivatives, a bulky porphyrinic substituent on the alkyne significantly increases the thermal barrier toward Bergman cyclization and leads to multiple photolysis products.

Full text of DOI:10.1016/j.tetlet.2006.10.164

Tetrahedron Letters 48 (2007) 725–728
Porphyrenediynes: synthesis and cyclization
of meso-enediynylporphyrins
a,b,
b
b
*
John D. Spence,
Amanda E. Hargrove, Hannah L. Crampton
b
and David W. Thomas
a
Department of Chemistry, California State University, Sacramento, 6000 J Street, Sacramento, CA 95819, United States
b
Department of Chemistry, Trinity University, One Trinity Place, San Antonio, TX 78212, United States
Received 29 August 2006; revised 17 October 2006; accepted 24 October 2006
Abstract—Synthetic methodology to prepare porphyrinylethynyl enediynes has been developed. Compared to phenylethynyl deriv-
atives, a bulky porphyrinic substituent on the alkyne significantly increases the thermal barrier toward Bergman cyclization and
leads to multiple photolysis products.
Ó 2006 Published by Elsevier Ltd.
The design and activation of enediyne pro-drugs that
cleave DNA upon Bergman cyclization remains a for-
porphyrin macrocycle can be readily functionalized to
serve as an improved delivery system imparting solubil-
ity, tumor delivery, and DNA binding properties to
1
midable synthetic challenge. The enediyne antitumor
antibiotics utilize complex molecular architectures to
control delivery and activation of enediyne warheads,
6
enediyne pro-drugs.
2
leading to their potent cytotoxicity. While the natural
The first example of a porphyrin-enediyne hybrid was
reported by the Smith group who prepared 2,3-di-
products and early synthetic models employ molecular
3
7
strain to control the cyclization event, recent synthetic
ethynylporphyrin 1 (Fig. 1). Upon heating to 190 °C,
efforts have focused on photochemical activation of sim-
1 undergoes thermal cyclization to afford picenoporphy-
rins via tandem radical cyclization with neighboring
meso-phenyl substituents. Zaleski and co-workers later
showed that this system cyclizes at room temperature
4
plified cyclic and acyclic enediynes. The prototypical
acyclic example is the cyclization of 1,2-bis(phenylethy-
nyl)benzene, which affords 2,3-diphenylnaphthalene
5
8
upon irradiation at 300 nm (Scheme 1). As part of
in the presence of DDQ and undergoes photocycliza-
9
our program to combine porphyrins with enediynes,
we have developed a methodology to incorporate por-
phyrinyl substituents on the enediyne alkyne. In addi-
tion to serving as a chromophore to potentially
promote photocyclization at longer wavelengths, the
tion via irradiation of the porphyrin Soret or Q bands.
Alternatively, phenylethynyl analogs afford only traces
9
of photocyclized adducts at elevated temperatures and
1
0
are prone to photoreduction of the macrocycle. We re-
cently reported the synthesis and reactivity of beta-ex-
tended porphyrenediyne 2 that undergoes traditional
Bergman cyclization followed by hydrogen atom
1
1
abstraction from 1,4-cyclohexadiene. More recently
Jones and co-workers reported the synthesis and
photocyclization of compound 3, which incorporates
meso-pyridyl substituents to aid delivery to biological
Ph
Ph
Ph
Ph
Ph
3
00 nm
iPrOH
1
2
targets. An alternative method to combine porphyrin
macrocycles with acyclic enediynes is to directly link
them to the alkyne as in 4. By connecting in this manner,
the chromophore can become conjugated to the in-plane
p-system of the enediyne isolated on the alkyne, whereas
1 and 2 are strictly conjugated to the enediyne out-of-
Ph
Scheme 1.
Keywords: Enediynes; Porphyrins; Bergman cyclization.
*
Corresponding author. Tel.: +1 916 278 4477; fax: +1 916 278
986; e-mail: jspence@csus.edu
1
3
4
plane p-system through the alkene. In this Letter, we
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.164

726
J. D. Spence et al. / Tetrahedron Letters 48 (2007) 725–728
N
Ph
M
Ph
NH
N
R
N
N
N
Mn
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
N
N
N
HN
Ph
Zn N
N
Ph
Ph
N
Ph
1
M = 2H, Ni, Zn
2
3
4a R = H
b R = Ph
4
Figure 1. Structures of porphyrenediynes.
report the synthesis of porphyrenediyne models 4a and
b and their respective thermal and photochemical
reactivities.
4a and 4b, a 1H singlet is observed for the lone remain-
ing meso-hydrogen near 10.3 ppm along with four 2H
doublets for the porphyrin beta-hydrogens ranging from
4
1
0.1 to 8.7 ppm. The remaining phenyl hydrogens are
The synthetic route toward meso-enediynylporphyrins
was adapted from the preparation of meso-ethynyl
observed from 8.3 to 7.4 ppm while the terminal alkyne
in 4a appears at 4.61 ppm. Similar shifts are observed in
1
4
1
porphyrins described by Dolphin. Coupling zinc(II)-
-iodo-10,20-diphenylporphyrin 5 with 1,2-diethynyl-
the H NMR spectrum of 8, with the exception of one
5
porphyrin beta-hydrogen shifted upfield to 7.73 ppm.
The lack of molecular symmetry in 4a and 4b was fur-
ther confirmed by the appearance of four distinct alkyne
1
5
16
benzene 6 or 1-ethynyl-2-(phenylethynyl)benzene 7
gave porphyrenediynes 4a and 4b, respectively, in 32%
and 58% yields (Scheme 2). THF was required as a sol-
vent for these reactions to improve solubility of the
iodoporphyrin, and optimal yields were obtained when
1
3
resonances between 100 and 80 ppm in C NMR spec-
troscopy. In the UV–visible absorbance spectrum of 4a
the porphyrin Soret band is red-shifted to 435 nm, com-
pared to 411 nm for zinc(II)-5,15-diphenylporphyrin,
with Q-bands noted at 561 and 603 nm. Similar trends
are observed in 4b with the Soret band shifted to
440 nm and Q-bands at 565 and 617 nm, while the Soret
band for diporphyrin 8 is observed at 424 nm. These
absorptions are consistent with a meso-ethynylporphy-
rin and demonstrate conjugation between the porphyrin
6
and 7 were slowly added to a solution of 5 to limit
self-coupling of the terminal alkynes. A second por-
phyrinic product, tentatively assigned as the bis-coupled
1
adduct 8 by H NMR, UV–visible and nominal mass
data, was also obtained from the reaction with 6 but
was too unstable to fully characterize.
1
17
18
The H NMR spectra of porphyrenediynes 4a and 4b
and enediyne p-system. Molecular modeling of 4b
readily confirmed their molecular structures. In both
indicates that the porphyrin macrocycle is rotated out
Ph
N
N Zn
N
N
H
Ph
Ph
Ph
6
N
N
Pd(PPh ) , CuI, Et N/THF
N
Zn N
N
Zn N
3
4
3
N
N
Ph
Zn
(
32%)
Ph
Ph
N
N
N
N
4a
8
I
Ph
Ph
Ph
5
7
Ph
N
N
Pd(PPh ) , CuI, Et N/THF
3
4
3
Zn N
(
58%)
N
Ph
4
b
Scheme 2.

J. D. Spence et al. / Tetrahedron Letters 48 (2007) 725–728
727
1
of the plane of the arenediyne and, as a result, the chro-
mophore is more efficiently conjugated to the in-plane
enediyne p-system isolated on the alkyne.
the red color of meso-aryl derivatives. The H NMR
spectrum shows the loss of the terminal alkyne signal
observed in 4a and the presence of three new aromatic
signals at 8.67, 8.41 and 8.08 ppm consistent with a
0
20
The thermal reactivity of porphyrenediynes 4a and 4b
toward Bergman cyclization in the solid state has been
investigated by differential scanning calorimetry
meso-(2 -naphthyl) substituent. The UV–visible spec-
trum shows a Soret band at 417 nm, which is blue-
shifted 18 nm compared to 4a as expected for the loss
of the meso-ethynyl group, with one prominent Q-band
observed at 545 nm. Furthermore, FAB HRMS gave a
molecular ion peak at m/z 650.1450, confirming the
addition of two hydrogen atoms. The increased steric
hindrance and higher temperature required for the ther-
molysis of 4b, however, led to degradation of the por-
phyrenediyne upon heating to 300 °C.
(
DSC). Although DSC has recently been shown to be
a very crude measure of relative reactivity for enediy-
1
9
nes, comparing porphyrenediynes 4a and 4b with their
respective starting terminal enediynes provides insight
into the steric demands imposed by porphyrin substitu-
tion. An irreversible exotherm indicative of Bergman
cyclization is observed for porphyrenediyne 4a begin-
ning at ꢀ230 °C (Fig. 2) while that of 6 is observed
beginning at ꢀ130 °C. In comparison, the onset temper-
ature for porphyrenediyne 4b is observed at ꢀ270 °C
whereas 7 displays an onset temperature at ꢀ150 °C.
Not surprisingly, adding a porphyrinyl substituent to
the terminal alkyne of 6 or 7 increases the onset temper-
ature by approximately 100–120 °C. In comparison,
adding one phenyl substituent (in going from 6 to 7) in-
creases the onset temperature by only 20 °C. Finally,
addition of two phenyl substituents, generating 1,2-
bis(phenylethynyl)benzene, increases the onset tempera-
ture to ꢀ280 °C.
The photochemical reactivity of 4a was next examined
by irradiation with 300 nm light in THF/iPrOH. How-
ever, no trace of cyclized product 9 is observed and
the starting porphyrenediyne is degraded within 5 h.
To demonstrate the ability of terminal enediynes to
photocyclize, irradiation of phenyl derivative 7 in iPrOH
at 300 nm for 5 h resulted in complete consumption of
the enediyne, and 2-phenylnaphthalene 10 was obtained
in 14% yield (Scheme 4). Under identical conditions, the
5
previously reported 1,2-bis(phenylethynyl)benzene re-
acts more slowly to produce 2,3-diphenylnaphthalene
in <10% yield with 20% recovered starting material. In
the photolysis of the phenylethynyl derivatives a signif-
icant amount of polymeric material is obtained as char-
acterized by a broad absorbance throughout the
To identify and characterize the Bergman cyclized prod-
uct, the solution reactivity of porphyrenediyne 4a in the
presence of a hydrogen atom donor was examined.
Heating a solution of porphyrenediyne 4a in 1,2,4-tri-
chlorobenzene containing 10% 1,4-cyclohexadiene
1
aromatic region in the crude H NMR spectrum.
(
CHD) at 250 °C for 96 h yielded the cyclized adduct 9
Irradiation of the Soret band of 4a with 419 nm light re-
sults in slow degradation of the porphyrenediyne with
>50% starting material recovered after 5 h along with
trace products and baseline material observed by TLC.
The limited reactivity of porphyrenediyne 4a compared
to 7 toward photo-Bergman cyclization underscores
in 26% yield after preparative thin layer chromatogra-
phy (Scheme 3). No other porphyrinoid products were
observed by TLC, UV or NMR analysis. During the
course of the reaction the solution changed from the
characteristic green color of meso-ethynylporphyrins to
9
the effect of steric bulk on the alkyne termini. However,
upon heating the photolysis reaction to 140 °C, trace
quantities of cyclized product 9 are observed by TLC
along with multiple colored products with nearly identi-
cal Rf values. In addition to the formation of 9, compet-
5
4
3
2
1
0
5
ing reactions such as alkyne reduction, porphyrin
9
,10
21
reduction,
fulvene formation and indene forma-
22
tion may be occurring. Recent theoretical calcula-
2
1
tions
suggest C1–C5 cyclization to fulvene
derivatives is competitive with C1–C6 Bergman cycliza-
tion when bulky groups are present at the alkyne ter-
mini, which may partly explain the formation of
multiple photolysis products from 4a compared to the
clean cyclization of 7. Similar results are obtained upon
irradiation of porphyrenediyne 4b with 419 nm light.
Mass analysis of the crude products obtained from pho-
100
200
300
400
o
Temperature ( C)
Figure 2. DSC scan of porphyrenediyne 4a.
H
o
2
50 C
Ph
H
Ph
1
,4-CHD
(26%)
N
3
00 nm
N
N
Zn N
N
Zn N
N
iPrOH
(14%)
N
Ph
Ph
Ph
Ph
4
a
9
7
10
Scheme 3.
Scheme 4.

728
J. D. Spence et al. / Tetrahedron Letters 48 (2007) 725–728
tolysis of 4a and 4b at 419 nm indicate formation of
multiple photoadducts with molecular weights two,
four, and six mass units higher than the starting mate-
rial, as expected for a mixture derived from competing
cyclization and reduction pathways.
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4
In conclusion, we have developed the syntheses of por-
phyrenediynes in which the porphyrin macrocycle is
conjugated to the in-plane p-system of an arenediyne.
The presence of a porphyrinic substituent on the alkyne
induces a large thermal barrier toward cyclization and
lowers the overall efficiency of the photo-Bergman cycli-
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competitive upon irradiation at 419 nm. In the presence
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Acknowledgements
This work was funded by grants from the Research Cor-
poration, Merck AAAS Undergraduate Science Re-
search Program and the California State University
Program for Education and Research in Biotechnology
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Experimental conditions and spectral data for com-
pounds 4a, 4b and 9 are available in Supplementary
data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.10.164.
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